US9650360B2

US9650360B2 - Anti-mycobacterial drugs against tuberculosis

Info

Publication number: US9650360B2
Application number: US14/388,404
Authority: US
Inventors: Vasu Nair; Maurice O. Okello; Machhindra G. Gund; Byung I. Seo; Pankajkumar R. Singh; Naveen K. Mangu
Original assignee: University of Georgia Research Foundation Inc UGARF
Current assignee: University of Georgia Research Foundation Inc UGARF
Priority date: 2012-03-31
Filing date: 2013-03-13
Publication date: 2017-05-16
Also published as: EP2831056A1; CN104254526B; EP2831056B1; WO2013148174A1; US20150050237A1; CN104254526A; EP2831056A4

Abstract

The present invention relates to the field of anti-mycobacterial therapeutics, in particular the treatment of tuberculosis, especially including pulmonary multidrug-resistant tuberculosis (MDR-TB), with applications in extensively drug-resistant tuberculosis (XDR-TB) and extremely drug-resistant tuberculosis (XXDR-TB), preferably in combination therapy.

Description

RELATED APPLICATIONS AND GRANT SUPPORT

This application is a United States national phase application claiming the benefit of priority from international application no. PCT/US2013/030687, of identical title, filed on Mar. 13, 2013 which claims the benefit of priority from provisional application Ser. No. 61/618,707, filed Mar. 31, 2012, of identical title, the entire contents of each of said applications being incorporated by reference in its entirety herein.

The present invention was supported in the early phases of discovery through support from the National Institutes of Health under grant R01 AI 43181. Consequently, the government has certain rights in the invention.

FIELD OF THE INVENTION

The present invention relates to the field of anti-mycobacterial therapeutics, in particular the treatment of pulmonary multidrug-resistant tuberculosis (MDR-TB), with applications in extensively drug-resistant tuberculosis (XDR-TB) and extremely drug-resistant tuberculosis (XXDR-TB), preferably in combination therapy.

BACKGROUND AND DISCUSSION OF THE INVENTION

Mycobacterium tuberculosis (TB) is a contagious, largely pulmonary, disease that is spread through the air. Only a small number of TB bacilli are needed to cause an infection. Almost a third of the world's population is currently infected with TB. Of the people who are infected with TB but who are not infected with HIV, some 5-10% become sick or are infectious at some period during their lifetime (WHO Fact Sheet, November, 2010, WHO report 2011: Global Tuberculosis Control). People with HIV are much more likely to develop TB. An estimated 1.7 million people died from TB in 2009. Also, multidrug-resistant M. tuberculosis, MDR-TB, is spreading [Orenstein, et al., Lancet Infect. Dis. 9, 153-161 (2009); Russell, et al., Science 328, 852-856 (2010); Dye, et al., Science 328, 856-861; (2010)]. Further complicating the TB picture worldwide is the emergence of extensively drug-resistant tuberculosis, XDR-TB and extremely drug-resistant tuberculosis, XXDR-TB (WHO: Drug Resistant TB, 2012).

However, there have been relatively few new agents discovered in the last 40 years to treat TB [Aristoff, et al., Tuberculosis 90, 94-118 (2010), Koul., et al., Nature 469, 483-490 (2100)]. Among the most used TB drugs are rifampin and its analogs, isoniazid, pyrazinamide, ethambutol and fluoroquinolone. The drug pipeline today is relatively thin with only 10 new or repurposed drugs in clinical trials [Zumla, et al., Nat. Rev. Drug Discov. 11, 171-172 (2012); New TB Drugs Website, 2011, online; Sundaramurthi, et al., Tuberculosis 92, 133-138 (2012); Luetkemeyer, et al., Am. J. Respir. Crit. Care Med. 184, 1107-1113 (2011); Lienhardt, et al., Curr. Opin. Pulm. Med. 16, 186-193 (2010); Ma, et al., Lancet, 375, 2100-2109 (2010)]. One of those drugs [bedaquiline, also referred to as R207910, TMC207, Andries, et al., Science 307, 223-227 (2005), Koul, et al., CA2529265A1; Porstmann, F. R., et al., WO2006125769A1; Brickner, S. J., et al., WO2010026526A1; Devito, et al., WO2011139832A2] was approved by the FDA in December 2012 as part of a combination treatment regimen for MDR-TB (NDA 204-384). Examples of other drugs in the clinical phase of development include: gatifloxacin [Ma, et al., Lancet 375, 2100-2109 (2010), He, et al., CN102198138A, Patel, et al., WO2011101710A1, Ismail, et al., WO2012057599A1]; moxifloxacin [Ji, et al., Antimicrob. Agents Chemother. 42, 2066-2069 (1998), Miyazaki, et al., Antimicrob. Agents Chemother. 43, 85-89 (1999), Alvirez-Freites, et al., Antimicrob. Agents Chemother. 46, 1022-1025 (2002), Bosche, et al., WO2000027398A1; McCarthy, et al., WO2003099229A2; Zeldis, et al., WO2010093588A1]; sudoterb [Ginsberg, Drugs 70, 2201-2214 (2010), Arora, et al., WO2004026828A1, Arora, et al., WO2006109323A1]; PNU100480 [Williams, et al., Antimicrob. Agents Chemother. 53, 1314-1319 (2009), Barbachyn, et al., WO9507271A1, Watts, et al., WO2002002121A2; Brickner, et al., WO2010026526A1, Wallis, WO2010122456A1]; AZD5847 [Williams, et al., Antimicrob. Agents Chemother. 53, 1314-1319 (2009), Kim, et al., WO2012144790A1]; SQ109 [Protopopova, et al., J. Antimicrob. Chemother. 56, 968-974 (2005), Sutcliffe, WO2007133803A2, Meng, Q., et al., CN101468958A]; OPC67683 [Singh, et al., Science 322, 1392-1395 (2008), Singh, et al., WO2007133803A2]; PA824 [Singh, et al., Science 322, 1392-1395 (2008), Sutcliffe, WO2007133803A2, Papadopoulou, et al., US20080076797A1, Singh, et al., WO2008005651A2, Devito, et al., WO2011139832A2].

MDR-TB is resistant to isoniazid and rifampin, the two drugs that are used commonly for drug-susceptible TB and with treatment-adherent TB patients. MDR-TB that has also developed resistance to one of the injectable second line TB drugs (kanamycin, capreomycin or amikacin) and also to a fluoroquinolone drug is classed as XDR-TB. XDR-TB can be treated with other second-line TB drugs, but the treatment is more difficult, more expensive and there may be more side effects. XXDR-TB is resistant to both first line and second line TB drugs and is extremely difficult to treat. In general, treatment for all drug-resistant TB can be complicated, lengthy and may be problematic, in part because of issues of toxicity.

Our research work on retroviral integrase inhibitors has led to the discovery of highly active compounds against a diverse set of primary HIV-1 isolates [Nair, et al., US 2012 0282218 A1, Nair, et al., PCT International Patent Application No. WO 2011/071849 A2, Nair, et al., ASM ICAAC Conference H2-801 (2011)]. In investigating the molecular modeling details of the mechanism of action of our active integrase inhibitors, it was apparent that these inhibitors had one common feature, i.e., they were all interacting with the DDE catalytic triad and also with two divalent magnesium ions in the catalytic core domain of HIV integrase. The DDE motif is essential for integrase catalysis [Nair, et al., Rev. Med. Virol. 17, 277-295 (2007), Nair, et al., J. Med. Chem. 49, 445-447 (2006), Frankel, et al., Annu. Rev. Biochem. 67, 1-25 (1998)]. However, our best integrase inhibitors of this class, while exhibiting potent anti-HIV activity [Nair, et al., US 2012 0282218 A1, Nair, et al., PCT International Patent Application No. WO 2011/071849 A2, Nair, et al., ASM ICAAC Conference H2-801 (2011], did not show as compelling a level of anti-MDR TB activity as the novel compounds of the current invention.

The catalytic core domain of DNA-dependent RNA polymerase (RNAP) of bacteria is conserved among cellular organisms [Archambault, et al., Microbiol. Mol. Biol Rev. 57, 703-724 (1993)]. Examination of the crystal structure [Zhang, et al., Cell 98, 811-824 (1999)] of the RNAP of Thermus acquaticus (a model for TB RNAP), with bound rifampin, a first-line drug for TB, shows that rifampin binds to the β-site on the RNAP and inhibits RNA synthesis by blocking the path of the elongating RNA, which is believed to be its mechanism of action [Campbell, et al., Cell 104, 901-912 (2001)]. However, there are other sites existing on TB RNAP that could be targeted by inhibitors to interfere with this RNAP's functional mechanism. For example, there is a pocket on the TB RNAP catalytic core domain that contains a structural region that bears some resemblance to the catalytic triad area of the catalytic core domain of HIV-1 integrase [Frankel, et al., Annu. Rev. Biochem. 67, 1-25 (1998), Cox and Nair, Antimicrob. Agents Chemother. 17, 343-353 (2006)]. This is the β′-site of this RNAP, which is close to 18 Å away from the binding location of rifampin in the β-site. Computational chemical biology and molecular modeling experiments revealed that our novel anti-TB compounds described in this invention are capable of binding inside the catalytic channel of the RNAP β′-pocket, interacting with a Mg²⁺ ion and a number of other residues in the β′-pocket, as well as with a few residues that are in the structural region that forms the interface between β′- and β-pockets. Our compounds appear to bind to the TB RNAP holoenzyme either before or after binding of the promoter DNA, which produces obstruction of transcription, resulting in failure of RNAP catalysis to initiate transcription. It is relevant to state that our compounds are not alternate substrates or transition state mimics of the RNAP polymerization reaction.

The new class of compounds described in this invention are multifunctional and are designed with the following structural components: dibenzyl pyridinone scaffold, diketo-enolic functionality, and a piperazine carboxamide moiety that carries an aromatic or substituted aromatic group on the second piperazine nitrogen. The compounds have been designed as treatments for MDR-TB and have therapeutic applications in XDR-TB and XXDR-TB. An example is shown below (Figure 1). This compound is active against MDR-TB with a minimum inhibitory concentration (MIC, i.e., the lowest concentration to completely inhibit growth of MDR-TB) of <1 microgram/mL (Agar dilution susceptibility method). In addition, this compound exhibits significant in vitro anti-HIV activity in cell culture with EC₉₀(concentration for 90% inhibition of virus replication) in the nM range.

SUMMARY OF THE INVENTION

Multifunctional compounds that have a dibenzyl pyridinone scaffold, a diketo/enolic functionality, a piperazine carboxamide moiety, and a N-substituted aromatic or substituted aromatic group on the piperazine ring and methods for their preparation and use are disclosed. The compounds are represented by Formula I and include tautomers, geometric isomers, regioisomers and pharmaceutically acceptable salts thereof, wherein the pyridinone scaffold and R and X groups are as otherwise defined in the specification. These complex multifunctional compounds exhibit substantial activity as novel anti-TB agents. The compounds are useful in the prevention and/or reducing the likelihood, inhibition or treatment of infection by MDR-TB, with applications in XDR-TB and XXDR-TB, and in the treatment of drug-resistant TB where there is also co-infection with HIV, either as the compounds, or as pharmaceutically acceptable salts, with pharmaceutically acceptable carriers, used alone or in combination with other anti-TB agents, anti-AIDS compounds, other antivirals, anti-infectives, immunomodulators, antibiotics, vaccines, and other therapeutic agents, which can be used to create combination anti-TB cocktails. Methods of treating, preventing and/or reducing the likelihood of drug-resistant TB and methods of treating or preventing infection by drug-resistant TB are also described, the method comprising administering one or more compounds according to the present invention, optionally in combination with additional agents, including anti-HIV agents, in effective amounts to a patient or subject in need.

Compounds according to the present invention exhibit one or more of the following characteristics desired in anti-TB compounds: high efficacy against MDR-TB and other drug-resistant TB, low toxicity, favorable hydrophobicity, appropriate distribution of polar surface area, enhanced stability to metabolic degradation and a favorable drug-drug interaction profile. The present compounds represent a material advance in the treatment and/or prevention of MDR-TB or other drug-resistant TB and related secondary conditions and/or disease states or accompanying co-infections with HIV.

Pharmaceutical compositions which include one or more compounds according to the present invention in combination with a pharmaceutically acceptable carrier, additive or excipient, optionally in combination with at least one additional agent as otherwise described herein represent an additional aspect of the invention. A kit comprising a pharmaceutical composition according to the present invention and instructions on how to administer the composition to a patient in need represent a further aspect of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The following terms are used throughout the specification to describe the present invention. Unless otherwise indicated, a term used to describe the present invention shall be given its ordinary meaning as understood by those skilled in the art.

The term “compound”, as used herein, unless otherwise indicated, refers to any specific chemical compound disclosed herein and includes tautomers and geometric isomers, as well as pharmaceutically acceptable salts thereof. Within its use in context, the term compound generally refers to a single chemically stable compound which can be administered to a patient or subject, but also may include other compounds such as tautomers and geometric isomers. The breadth of the term “compound” shall be construed within the context of the use of the term. It is noted that where a substituent should be present in context but is not specifically signified, it is understood that such substituent represents a hydrogen (H) atom.

The term “patient” or “subject” is used throughout the specification to describe an animal, generally a mammal and preferably a human, to whom treatment, including prophylactic treatment, with the compositions according to the present invention is provided. For treatment of those infections, conditions or disease states which are specific for a specific animal such as a human patient, the term patient refers to that specific animal.

The term “effective” is used herein, unless otherwise indicated, to describe an amount of a compound or composition or component which, in context, is used to produce or effect an intended result, whether that result relates to the treatment of a microbial, viral or other disease state, disorder or condition associated with TB or alternatively, is used to produce another compound, agent or composition. This term subsumes all other effective amount or effective concentration terms which are otherwise described in the present application.

The term “scaffold” is used to mean a dibenzyl pyridinone chemical structure. The dibenzyl group has R₁, R₂, R₃and R₄substituents which are as defined herein. The scaffold contains additional functionalities including a diketo-enol group and a substituted piperazine carboxamide moiety of which the X groups are as defined herein.

The term “minimum inhibitory concentration” is defined as the lowest concentration of an anti-mycobacterial compound that will inhibit completely the growth of the microorganism as visibly discerned after a delineated period.

The term “prevention” is used within context to mean “reducing the likelihood” of a condition or disease state from occurring as a consequence of administration or concurrent administration of one or more compounds or compositions according to the present invention, alone or in combination with another agent. Thus, the term prevention is used within the context of a qualitative measure and it is understood that the use of a compound according to the present invention to reduce the likelihood of an occurrence of a condition or disease state as otherwise described herein will not be absolute, but will reflect the ability of the compound to reduce the likelihood of the occurrence within a population of patients or subjects in need of such prevention.

The term “multi-drug resistant Mycobacterium tuberculosis,” which is referred to with the acronym, MDR-TB, describes tuberculosis that is resistant to isoniazid and rifampin, the two drugs that are used commonly for drug-susceptible TB and with treatment-adherent TB patients.

The term “extensively drug-resistant Mycobacterium tuberculosis,” which is referred to with the acronym, XDR-TB, describes MDR-TB that has also developed resistance to one or more of the injectable second line TB drugs (kanamycin, capreomycin or amikacin) and also to a fluoroquinolone drug. The term “extremely drug-resistant Mycobacterium tuberculosis,” referred to as XXDR-TB, is TB that is resistant to both first line and second line TB drugs.

The term “human immunodeficiency virus” or “HIV” shall be used to describe human immunodeficiency viruses 1 and 2 (HIV-1 and HIV-2). The terms “ARC” and “AIDS” refer to syndromes of the immune system caused by the human immunodeficiency virus, which are characterized by susceptibility to certain diseases and T cell counts which are depressed compared to normal counts. HIV progresses from Category 1 (Asymptomatic HIV Disease) to Category 2 (ARC), to Category 3 (AIDS), with the severity of the disease.

The term “coadministration” shall mean that at least two compounds or compositions are administered to the patient at the same time, such that effective amounts or concentrations of each of the two or more compounds may be found in the patient at a given point in time. Although compounds according to the present invention may be co-administered to a patient at the same time, the term embraces both administration of two or more agents at the same time or at different times, provided preferably that effective concentrations of coadministered compounds or compositions are found in the subject at a given time. The term coadministration also encompasses, in certain instances, the serial administration of agents which are administered serially in a patient to produce an intended effect, regardless of the time of administration and concentration of agent found in the subject.

The term “independently” is used herein to indicate that a variable, which is independently applied, varies independently from application to application.

The present invention is directed to compounds of the general molecular Formula below, including tautomer, geometric isomer and pharmaceutically acceptable salts thereof. The groups labeled as A and B represent unsubstituted and fluoro-substituted phenyl rings, with substitutions from mono- through to tetra-substituted, involving the ortho, meta and para positions (with reference to the methylene group to which the phenyl group is bound), and combinations thereof. The groups attached to the piperazine ring nitrogen and labeled as X are aromatic groups which term includes heteroaromatic groups. The groups R and X are as otherwise described in the specification.

Particular compounds of Formula I with respect to phenyl rings labeled A and B, which also carry the group X substitutions, include the following:

- R₁=H, R₂=H, R₃=H, R₄=H
- R₁=H, R₂=o-F, R₃=o-F, R₄=p-F
- R₁=o-F, R₂=o-F, R₃=o-F, R₄=m-F
- R₁=o-F, R₂=o-F, R₃=o-F, R₄=p-F
- R₁=o-F, R₂=o-F, R₃=m-F, R₄=m-F
- R₁=o-F, R₂=o-F, R₃=m-F, R₄=p-F
- R₁=o-F, R₂=m-F, R₃=m-F, R₄=p-F
- R₁=H, R₂=m-F, R₃=m-F, R₄=p-F
- R₁=m-F, R₂=o-F, R₃=o-F, R₄=m-F
- R₁=m-F, R₂=o-F, R₃=o-F, R₄=p-F
- R₁=m-F, R₂=o-F, R₃=m-F, R₄=m-F
- R₁=m-F, R₂=o-F, R₃=m-F, R₄=p-F
- R₁=m-F, R₂=m-F, R₃=m-F, R₄=p-F
- R₁=H, R₂=o-F, R₃=o-F, R₄=m-F
- R₁=p-F, R₂=o-F, R₃=o-F, R₄=m-F
- R₁=p-F, R₂=o-F, R₃=o-F, R₄=p-F
- R₁=p-F, R₂=o-F, R₃=m-F, R₄=m-F
- R₁=p-F, R₂=o-F, R₃=m-F, R₄=p-F
- R₁=p-F, R₂=m-F, R₃=m-F, R₄=p-F
- R₁=o-F, R₂=m-F, R₃=m-F, R₄=H
- R₁=o-F, R₂=p-F, R₃=H, R₄=H and
- R₁=o-F, R₂=o-F, R₃=o-F, R₄=H
  By way of convention, o-F represents ortho substituted fluorine, m-F represents meta substituted fluorine and p-F represents para substituted fluorine.

Particular compounds of Formula I with respect to group X which are directed to optionally substituted aromatic groups, including heteroaryl groups, preferably include the following groups. These also carry the substitutions shown above in the rings A and B. These preferred X groups are as follows:

Also embraced by the present invention are pharmaceutical compositions useful for the treatment of MDR-TB, comprising an effective amount of at least one compound of this invention as described herein, and a pharmaceutically acceptable carrier, additive or excipient. Pharmaceutical compositions useful for treating infection by drug-resistant TB or for treating, in combination with other drugs, MDR-TB co-infections such as those with HIV, are included by the present invention. In addition, the present invention is directed to a pharmaceutical composition comprising, in effective combination, a therapeutically effective amount of at least one compound of the present invention and a suitable and effective combination with: (i) one or more other TB drugs, including drugs against resistant TB; (ii) a therapeutically effective amount of an agent(s) for the treatment of AIDS; (iii) an anti-infective agent, (iv) an immunomodulator, (v) other useful therapeutic agents, including antibiotics, vaccines and other antiviral agents.

Other applications are also part of this invention. For example, the compounds of this invention may also be useful for treatments of drug resistant forms of TB, including XDR-TB and XXDR-TB and in combination therapeutic treatment for these resistant TB infections as well as co-infections involving HIV and other viral infections.

The compounds of the present invention also embrace geometric isomers and these forms are also included in the present invention.

Tautomeric forms may also exist with compounds of the present invention. Thus, the terminology “and tautomers thereof” is used in describing tautomeric forms of compounds of Formula I such as Ia and Ib (shown below). By naming compounds as being represented by the general Formula I and tautomers thereof, it is understood that for the purposes of the present invention, that tautomers 1a and 1b are also included. Similarly, by referring to compound (1a), it is understood for the purposes of the present application that tautomers (1) and (1b) are also intended to be included. The same holds true for references to tautomer (1b).

When the variables involving R₁, R₂, R₃, and R₄occur more than once in any Formula I, the definition on each occurrence is independent of its definition at every other occurrence. Combinations of pyridinones and R and X variables are permissible only if, in context, such combinations result in stable compounds.

For the X groups, the term “aromatic,” in context, refers to a substituted or unsubstituted aromatic group having a single ring (e.g., benzene) or multiple condensed rings (e.g., naphthyl, anthracenyl, phenanthryl).

Particular compounds of Formula I include:

1. 4-(1,5-dibenzyl-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione
2. 1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1,5-dibenzyl-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
3. 4-(1,5-dibenzyl-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione
4. 4-(1,5-dibenzyl-2-oxo-1,2-dihydropyridin-3-yl)-1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-hydroxybut-3-ene-1,2-dione
5. 1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1,5-dibenzyl-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
6. 1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1,5-dibenzyl-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
7. 1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1,5-dibenzyl-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
8. 1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1,5-dibenzyl-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
9. 4-(1-(2-fluorobenzyl)-5-(4-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione
10. 1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-5-(4-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
11. 4-(1-(2-fluorobenzyl)-5-(4-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione
12. 1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-5-(4-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
13. 1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-5-(4-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
14. 1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-5-(4-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
15. 1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-5-(4-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
16. 1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-5-(4-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
17. 4-(5-(2,6-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione
18. 4-(5-(2,6-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione
19. 1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(5-(2,6-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
20. 4-(5-(2,6-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-hydroxybut-3-ene-1,2-dione
21. 1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(5-(2,6-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
22. 1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(5-(2,6-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
23. 1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(5-(2,6-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
24. 1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(5-(2,6-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
25. 4-(5-(3,5-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione
26. 1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(5-(3,5-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
27. 4-(5-(3,5-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione
28. 4-(5-(3,5-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-hydroxybut-3-ene-1,2-dione
29. 1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(5-(3,5-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
30. 1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(5-(3,5-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
31. 1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(5-(3,5-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
32. 1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(5-(3,5-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
33. 4-(1-benzyl-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione
34. 1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1-benzyl-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
35. 4-(1-benzyl-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione
36. 4-(1-benzyl-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-hydroxybut-3-ene-1,2-dione
37. 1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-benzyl-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
38. 1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-benzyl-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
39. 1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-(4-(1-benzyl-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
40. 1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-benzyl-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
41. 4-(1-(2-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione
42. 1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
43. 4-(1-(2-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione
44. 1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
45. 1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
46. 1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
47. 1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
48. 1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
49. 4-(1-(4-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione
50. 1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1-(4-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
51. 4-(1-(4-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(15naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione
52. 1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-(1-(4-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
53. 1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-(4-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
54. 1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(4-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
55. 1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(4-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
56. 1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(4-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
57. 4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione
58. 1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
59. 4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione
60. 1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
61. 1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
62. 1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
63. 1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
64. 1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
65. 4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione
66. 1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
67. 4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione
68. 1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
69. 1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
70. 1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
71. 1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
72. 1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
73. 4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione
74. 1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
75. 4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione
76. 1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
77. 1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
78. 1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
79. 1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
80. 1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
81. 4-(1-(2-fluorobenzyl)-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione
82. 1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
83. 4-(1-(2-fluorobenzyl)-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione
84. 1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
85. 1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
86. 1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
87. 1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
88. 1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
89. 4-(1-benzyl-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione
90. 1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1-benzyl-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
91. 4-(1-benzyl-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione
92. 4-(1-benzyl-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-hydroxybut-3-ene-1,2-dione
93. 1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-benzyl-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
94. 1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-benzyl-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
95. 1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1-benzyl-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
96. 1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-benzyl-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
97. 4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione
98. 1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
99. 4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalene-1-yl)piperazin-1-yl)but-3-ene-1,2-dione
100. 1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
101. 1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
102. 1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
103. 1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
104. 1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
105. 4-(1-(3-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione
106. 1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
107. 4-(1-(3-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalene-1-yl)piperazin-1-yl)but-3-ene-1,2-dione
108. 1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
109. 1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
110. 1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
111. 1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
112. 1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
113. 4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione
114. 1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
115. 1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
116. 4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione
117. 1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
118. 1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
119. 1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
120. 1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
121. 4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione
122. 1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
123. 4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione
124. 1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
125. 1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
126. 1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
127. 1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
128. 1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione

Therapeutically effective amounts of the compounds of the present invention may be administered to patients orally, including buccally, parenterally, by inhalation spray, topically, or rectally, in dosage unit formulations containing pharmaceutically-acceptable carriers, adjuvants and vehicles including nanoparticle drug delivery approaches. The term “pharmaceutically acceptable” is meant to infer that the carrier, diluent, excipient or other additive is biologically compatible with the other ingredients of the formulation and not deleterious to the patient or recipient. Pharmaceutical compositions are in pharmaceutical dosage form and may be administered in the form of orally-administrable suspensions or tablets, nasal sprays and injectable preparations (injectable aqueous or oleagenous suspensions or suppositories). This method of treatment is part of the invention. The administration approaches used (e.g., orally as solution or suspension, immediate release tablets, nasal aerosol or inhalation, injectable solutions or suspensions or rectally administered in the form of suppositories) involve techniques that are well-known in the art of pharmaceutical formulation.

The compounds of this invention can be administered orally to humans in a preferred form (such as tablets) and in an effective amount within a preferred dosage range. The specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including compound activity, compound metabolism and duration of action, patient age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the condition of the patient undergoing therapy.

The present invention also includes therapeutically effective combinations of compounds of formula I with one or more other therapeutic agents such as other anti-TB drugs, AIDS antivirals, other antiviral agents, immunomodulators, anti-infectives, antibiotics, vaccines or other therapeutic agents. Some examples are given below.

Anti-TB Drugs, Antiviral Agents, Anti-Infectives, Immunomodulators, Opportunistic Infection Drugs, Other Relevant Drugs TB Treatments and TB Co-Infections


Drug Name	Manufacturer Examples	Therapeutic Use

Rifampin (Rifadin,	Sanofi Aventis LLC US	TB and TB-related
Rimactane)		mycobacterial infections
Rifapentine	Sanofi Aventis LLC US	TB
Isoniazid (Nydrazid)	Bristol Myers Squibb	TB
	Eli Lilly
	Hoffmann La Roche Inc.
	Novartis
	Sandoz Inc.
Ethambutol	Barr laboratories Inc.	Adjunct, in the treatment
	STI Pharma LLC	TB
	West ward
	pharmaceutical corp.
Ethionamide	Wyeth Inc.	TB
Para-aminosalicylic	Bristol Myers Squibb Co.	TB
acid (PAS)
Capreomycin	Akorn Inc.	Treatment of TB in
		combination with other
		drugs.
Amikacin	Abbott	Mycobacterium avium and M. tb.
Rifabutin (Mycobutin)	Pharmacia	Disseminated Mycobacterium
		avium complex (MAC)
		disease in patients with
		advanced HIV infection.
Streptomycin	Eli Lilly, Pfizer	TB
Pyrazinamide	Dava Inc., Mikart Inc.	Initial treatment of active
		TB in adults and children
		when combined with other
		TB agents
Cycloserine	Purdue GMP Center	Used in combination with
	LLC, Chao Center	other drugs to treat
	Industrial pharmacy	Mycobacterium avium
		complex (MAC) and TB.
Ciprofloxacin	Bayer, Teva, Baxter,	TB and other infections
	Ranbaxy, Sandoz Inc.	caused by susceptible
		organisms.
Ofloxacin	Ortho McNeil, Sandoz	TB and accompanying
	Inc., Ranbaxy, Teva	infections.
Levofloxacin	Ortho McNeil	TB and accompanying
		infections.
Clofazimine	Novartis	TB
Bedaquiline	Johnson & Johnson	Multidrug-resistant TB
		(MDR TB)
097	Hoechst/Bayer	HIV infection, AIDS,
		ARC (NNRT inhibitor)
Amprenivir	Glaxo Wellcome	HIV infection, AIDS,
141W94, GWI41		ARC (protease inhibitor)
Abacavir (1592U89)	Glaxo Wellcome	HIV infection, AIDS,
GW 1592		ARC (RT inhibitor)
Acemannan	Carrington Labs (Irving,	ARC
	TX)
Acyclovir	Burroughs Wellcome	HIV infection, AIDS,
		ARC, in combination with
		AZT
AD-439	Tanox Biosystems	HIV infection, AIDS,
		ARC
AD-519	Tanox Biosystems	HIV infection, AIDS,
		ARC
Adefovir dipivoxil AL-	Gilead Sciences	HIV infection
721	Ethigen (Los Angeles,	ARC, PGL HIV positive,
	CA)	AIDS
Alpha Interferon	Glaxo Wellcome	Kaposi's sarcoma, HIV in
		combination w/Retrovir
Ansamycin LM427	Adria Laboratories	ARC
	(Dublin, OH)
	Erbamont (Stamford, CT)
Antibody which	Advanced Biotherapy	AIDS, ARC
neutralizes pH labile	Concepts (Rockville,
alpha aberrant	MD)
Interferon
AR 177	Aronex Pharm	HIV infection, AIDS,
		ARC
Beta-fluoro-ddA	National Cancer Institute	AIDS-associated diseases
BMS-232623,	Bristol-Myers	HIV infection, AIDS,
(CGP-73547)	Squibb/Novartis	ARC (protease inhibitor)
BMS-234475	Bristol-Myers	HIV infection, AIDS,
(CGP-61755)	Squibb/Novartis	ARC (protease inhibitor)
		HIV infection, AIDS,
		ARC (protease inhibitor)
CI-1012	Warner-Lambert	HIV-1 infection
Cidofovir	Gilead Science	CMV retinitis, herpes,
		Papillomavirus
Curdlan sulfate	AJI Phanna USA	HIV infection
Cytomegalovirus	MedImmune	CMV retinitis
Immune globin
Cytovene	Syntex	Sight threatening CMV
Ganciclovir		Peripheral CMV
		Retinitis
ddI	Bristol-Myers Squibb	HIV infection, AIDS,
Dideoxyinosine		ARC; combination with
		AZT/d4T
DMP-450	AVID (Camden, NJ)	HIV infection, AIDS,
		ARC (protease inhibitor)
Efavirenz (DMP-266)	DuPont Merck	HIV infection, AIDS,
		ARC (non-nucleoside RT
		Inhibitor
EL10	Elan Corp, PLC	HIV infection
	(Gainesville, GA)
Famciclovir	Smith Kline	Herpes zoster, herpes
		simplex
FTC	Emory University	HIV infection, AIDS,
		ARC (reverse transcriptase
		inhibitor)
GS 840	Gilead	HIV infection, AIDS,
		ARC (reverse transcriptase
		inhibitor)
HBY097	Hoechst Marion Roussel	HIV infection, AIDS,
		ARC (non-nucleoside
		reverse transcriptase
		inhibitor)
Hypericin	VIMRx Phann.	HIV infection, AIDS,
		ARC
Recombinant Human	Triton Biosciences	AIDS, Kaposi's sarcoma,
Interferon Beta	(Almeda, CA)	ARC
Interferon alfa-n3	Interferon Sciences	ARC, AIDS
Indinavir	Merck	HIV infection, AIDS,
		ARC, asymptomatic HIV
		positive; combination with
		AZT/ddI/ddC
Isentress (Raltegravir)	Merck	HIV infection, AIDS,
		ARC (integrase inhibitor)
ISIS-2922	ISIS Pharmaceuticals	CMV retinitis
KNI-272	Natl. Cancer Institute	HIV-associated diseases
Lamivudine, 3TC	Glaxo Wellcome	HIV infection, AIDS,
		ARC (reverse transcriptase
		inhibitor); also with AZT
Lobucavir	Bristol-Myers Squibb	CMV infection
Nelfinavir	Agouron	HIV infection, AIDS,
	Pharmaceuticals	ARC (protease inhibitor)
Nevirapine	Boeheringer Ingleheim	HIV infection, AIDS,
		ARC (RT inhibitor)
Novapren	Novaferon Labs, Inc.	HIV inhibitor
	(Akron, OR)
Peptide T	Peninsula Labs	AIDS
Octapeptide Sequence	(Belmont, CA)
Trisodium	Astra Pharm. Products	CVV retinitis, HIV
Phosphonoformate.	Inc,	infection, other CMV
PNU-140690	Pharmacia Upjohn	HIV infection, AIDS,
		ARC (protease inhibitor)
Probucol	Vyrex	HIV infection, AIDS
RBC-CD4	Sheffield Med. Tech	HIV infection, AIDS,
	(Houston, TX)	ARC
Ritonavir	Abbott	HIV infection, AIDS,
		ARC (protease inhibitor)
Saquinavir	Roffmann-LaRoche	HIV infection, AIDS,
		ARC (protease inhibitor)
Stavudine; d4T	Bristol-Myers Squibb	HIV infection, AIDS,
Didehydrodeoxythy-		ARC
midine
Valaciclovir	Glaxo Wellcome	Genital HSV & CMV
		infections
Virazole Ribavirin	Viratek/ICN (Costa	Asymptomatic HIV
	Mesa, CA)	positive, LAS, ARC
VX-478	Vertex	HIV infection, AIDS,
		ARC
Zalcitabine	Hoffmann-LaRoche	HIV infection, AIDS,
		ARCwithAZT
Zidovudine; AZT	Glaxo Wellcome	HIV infection, AIDS,
		ARC, Kaposi's sarcoma, in
		combination with
		other therapies
Tenofovir diisoproxil	Gilead	HIV infection, AIDS,
fumarate salt (Viread ®)		(RT inhibitor)
Combivir ®	GSK	HIV infection, AIDS,
		(RT inhibitor)
Abacavir succinate (or	GSK	HIV infection, AIDS,
Ziagen ®)		(reverse transcriptase
		inhibitor)
Fuzeon ® (or T-20)	Roche/Trimeris	HIV infection, AIDS,
		viral Fusion inhibitor
AS-101	Wyeth-Ayerst	AIDS
Bropirimine	Pharmacia Upjohn	Advanced AIDS
Acemannan	Carrington Labs, Inc.	AIDS, ARC
	(Irving, TX)
CL246,738	American Cyanamid	AIDS, Kaposi's sarcoma
	Lederle Labs
EL10	Elan Corp, PLC	HIV infection
	(Gainesville, GA)
FP-21399	Fuki Immuno PHARM	Blocks HIV fusion with
		CD4 + cells
Gamma Interferon	Genentech	ARC, in combination
		w/TNF
Granulocyte	Genetics Institute	AIDS
Macrophage Colony	Sandoz
Stimulating Factor
Granulocyte	Hoeschst-Roussel	AIDS
Macrophage Colony	Immunex
Stimulating Factor
Granulocyte	Schering-Plough	AIDS, combination
Macrophage Colony		w/AZT
Stimulating Factor
HIV Core Particle	Rorer	Seropositive HIV
Immunostimulant
IL-2	Cetus	AIDS, in combination
Interleukin-2		w/AZT
IL-2	Hoffman-LaRoche	AIDS, ARC, HIV, in
		Interleukin-2 1mmunex
		combination w/AZT
IL-2 lnterleukin-2	Chiron	AIDS, increase in CD4
(aldeslukin)		cell counts
Immune Globulin	Cutter Biological	Pediatric AIDS, in
(human)	Intravenous	combination w/AZT
	(Berkeley, CA)
IMREG-1	Imreg (New Orleans,	AIDS, Kaposi's sarcoma,
	LA)	ARC, PGL
IMREG-2	Imreg (New Orleans,	AIDS, Kaposi's sarcoma,
	LA)	ARC, PGL
Imuthiol Diethyl	Merieux Institute	AIDS, ARC
Dithio Carbamate
Alpha-2 Interferon	Schering Plough	Kaposi's sarcoma w/AZT,
		AIDS
Methionine-Enkephalin	TNI Pharmaceutical	AIDS, ARC
	(Chicago, IL)
MTP-PE	Ciba-Geigy Corp.	Kaposi's sarcoma
Muramyl-Tripeptide
Granulocyte	Amgen	AIDS, in combination
Colony Stimulating		w/AZT
Factor
Remune	Immune Response Corp.	Immunotherapeutic
rCD4	Genentech	AIDS, ARC
Recombinant Soluble
Human CD4-IgG
rCD4-IgG Hybrids		AIDS, ARC
Recombinant Soluble	Biogen	AIDS, ARC
HumanCD4
Interferon Alfa 2a	Hoffman-LaRoche	Kaposi's sarcoma, AIDS,
		AR, combination w/AZT
SK&F1-6528	Smith Kline	HIV infection
Soluble T4
Thymopentin	Immunobiology	HIV infection
	Research Institute
	(Annandale, NJ)
Tumor Necrosis Factor	Genentech	ARC, in combination
(TNF)		w/gamma Interferon
AK602	Kumamoto University	HIV infection (entry and
	Japan	fusion inhibitor)
Alovudine	Medivir, UK Ltd.	HIV infection (nucleoside
		RT inhibitor)
Amdoxovir	RFS Pharma, LLC	Treatment of HIV and
		HBV infections
		(nucleoside RT Inhibitor)
AMD070	AnorMED, Inc.	HIV infection (entry and
		fusion inhibitor)
Atazanavir (Reyataz)	Bristol-Myers Squibb	HIV infection (protease
		inhibitor)
AVX754 (apricitabine)	Avexa Ltd.	HIV infection (nucleoside
		RT inhibitor)
Bevirimat	Panacos Pharmaceuticals	HIV infection (maturation
		inhibitor)
BI-201	Biolnvent	HIV infection (gene
		therapy, blocks HIV tat
		gene).
BMS-378806	Bristol-Myers Squibb	HIV infection (entry
		inhibitor)
BMS-488043	Bristol-Myers Squibb	HIV infection (entry and
		fusion inhibitor)
BMS-707035	Bristol-Myers Squibb	HIV infection (integase
		inhibitor)
C31G	Cellegy Inc.	Pharmaceuticals, HIV
		infection and other
		sexually transmitted
		diseases (STDs)
Carbopol 974P	ReProtect, LLC	Sexual transmission of
		HIV
Calanolide A	Sarawak MediChem	HIV infection (non-
	Pharmaceuticals, Inc.	nucleoside RT inhibitor)
Carrageenan	FMC Biopolymer	HIV microbicide
Cellulose sulfate	Polydex	Prevention of HIV
	Pharmaceuticals, Ltd.	infection and other
		sexually transmitted
		diseases
Cyanovirin-N	Cellegy Pharmaceuticals,	Prevention of sexual
	Inc.	transmission of HIV
		infection
Darunavir	Tibotec	HIV infection
		(coadministered with
		ritonavir)
Delavirdine	Pfizer	HIV infection
		(nonnucleoside
		RT inhibitor)
Dextran sulfate	Ueno Fine Chemicals	Prevention of transmission
	Industry, Ltd.	of HIV
Didanosine (Videx,	Bristol-Myers Squibb	HIV infection (nucleoside
Videx EC)		RT inhibitor)
Efavirenz	Bristol-Myers Squibb	HIV infection
		(nonnucleoside RT
		inhibitor)
Elvucitabine	Achillion	HIV infection
		Pharmaceuticals
		(nucleoside RT inhibitor)
Emtricitabine	Gilead Sciences	HIV infection (nucleoside
		RT inhibitor)
Fosamprenavir	GlaxoSmithKline	HIV infection (protease
(Lexiva)		inhibitor)
Fozivudine tidoxil	Heidelberg Pharma	HIV infection (entry and
		fusion inhibitor)
Elvitegravir	Gilead Sciences	HIV infection (integase
		inhibitor)
GSK-873, 140	GlaxoSmithKline	HIV infection (entry and
(aplaviroc)		fusion inhibitor)
GSK-364735	Glaxo SmithKline	HIV infection (integase
		inhibitor)
GW640385	GlaxoSmithKline	HIV infection (protease
(brecanavir)		inhibitor)
HG0004	Human Genome	HIV infection (entry and
	Sciences	fusion inhibitor)
HGTV43	Enzo Therapeutics	HIV infection (antisense
		drug)
Hydroxyethyl cellulose	Union Carbide	Prevent sexual
		transmission of HIV
INCB9471	Incyte Corporation	HIV infection (entry and
		fusion inhibitor)
KP-1461	Koronis Pharmaceuticals	HIV infection (nucleoside
		RT inhibitor)
Lopinavir	Abbott Laboratories	HIV infection (protease
		inhibitor)
Mifepristone	Viral Genomix	HIV infection (gene
(VGX410, RU486)		therapy,interferes with
		vpr)
MK-0518	Merck	HIV infection (integase
		inhibitor)
PA-457 (bevirimat)	Panacos	Treatment of HIV
	Pharmaceuticals, Inc.	(maturation inhibitor)
Poly(I)-Poly(C12U)	Hemispherx Biopharma,	Biological response
(Ampligen)	Inc.	modifier
PPL-100	Merck	HIV infection (protease
		inhibitor)
PRO 140	Progenics	HIV infection (entry and
	Pharmaceuticals, Inc.	fusion inhibitor)
PRO 542	Progenics	HIV infection (entry and
	Pharmaceuticals, Inc.	fusion inhibitor)
PRO 2000	Indevus Pharmaceuticals,	Microbicide
	Inc.
Racivir	Pharmasset, Inc.	HIV infection (nucleoside
		RT inhibitor)
SCH-D (vicriviroc)	Schering-Plough Corp	HIV infection (entry and
		fusion inhibitor)
SP01A	Samaritan	HIV infection (entry and
	Pharmaceuticals	fusion inhibitor)
SPL7013	Starpharma	Microbicide
TAK-652	Takeda	HIV infection (entry and
		fusion inhibitor)
Tipranavir (Aptivus)	Boehringer Ingelheim	HIV infection (protease
	Pharmaceuticals	inhibitor)
TNX-355	Tanox, Inc.	HIV infection (entry and
		fusion inhibitor)
TMC125 (etravirine)	Tibotec	HIV infection (non-
		nucleoside RT inhibitor)
UC-781	Cellegy Pharmaceuticals,	Microbicide
	Inc
UK-427,857	Pfizer	HIV infection (entry and
(Maraviroc)		fusion inhibitor)
Valproic acid	Abbott	Treating seizures in HIV
		infection
VRX496	VIRxSYS	Gene therapy
Zalcitabine (Hivid)	Roche	HIV infection (nucleoside
		T inhibitor)
Valganciclovir	Roche	Antiviral (CMV retinitis in
(Valcyte)		AIDS)
Clindamycin with	Pharmacia Upjohn	PCP
Primaquine
Fluconazole	Pfizer	Cryptococcal meningitis,
		candidiasis
Pastille	Squibb Corp.	prevention of oral
Nystatin Pastille		candidiasis
Ornidyl	Merrell Dow	PCP
Eflornithine
Pentamidine	LyphoMed (Rosemont,	PCP treatment
Isethionate (IM & IV)	IL)
Trimethoprim		Antibacterial
Trimethoprim/sulfa		Antibacterial
Piritrexim	Burroughs Wellcome	PCP treatment
Pentamidine isethionate	Fisons Corporation	PCP prophylaxis
Spiramycin	Rhone-Poulenc	Cryptosporidial diarrhea
Intraconazole-R51211	Janssen Pharm	Histoplasmosis;
		cryptococcal meningitis
Trimetrexate	Warner-Lambert	PCP
Daunorubicin	NeXstar, Sequus	Karposi's sarcoma
Recombinant Human	Ortho Pharm. Corp.	Severe anemia assocated
Erythropoietin		w/AZT therapy
Recombinant Human	Serono	AIDS-related wasting,
Growth Hormone		cachexia
Megestrol Acetate	Bristol-Myers Squibb	Treatment of anorexia
		associated w/AIDS
Testosterone	Alza, Smith Kline	AIDS-related wasting
Total Enteral Nutrition	Norwich Eaton	Diarrhea and
	Pharmaceuticals	malabsorption in AIDS
Aldesleukin	Chiron Corp	Biological response
(Proleukin)		modifier
Amphotericin B	Pfizer, Bristol-Myers	Antifungal
(Abelecet,	Squibb
AmBisome, Amphocin,
Amphotec, Fungizone)
Azithromycin	Pfizer	Antibacterial antibiotic
(Zithromax)
Calcium	Bioform Medical, Inc.	Dermal filler
hydroxyapatite
(Radiesse
Doxorubicin	Ortho Biotech, Alza	Antineoplastic
(liposomal) (Doxil)	Corporation
Dronabinol (Marinol)	Unimed Pharmaceuticals,	Antiemetics
	Inc.
Entecavir (Baraclude)	Bristol-Myers Squibb	Antiviral
Epoetin alfa (Epogen,	Ortho Biotech	Anemia
Procrit)
Etoposide (Etopophos	Pfizer, Bristol-Myers	Antineoplastic
(phosphate salt),	Squibb
Toposar, VePesid)
Fluconazole (Diflucan)	Pfizer	Antifungal
Interferon alfa-2	Roche, Schering-Plough	Biological response
(Intron A (2b),		modifiers
Roferon-A (2a)
Itraconazole	Ortho Biotech, Janssen	Antifungal
(Sporanox)	Pharmaceutica
Megestrol (Megace,	Bristol-Myers Squibb	Anticachectic
Megace ES)
Paclitaxel (Onxol,	Bristol-Myers Squibb,	Antineoplastic
Taxol)	IVAX Pharmaceuticals
Peginterferon alfa-2	Roche, Schering-Plough	Antiviral
(PEG-Intron (2b),
Pegasys (2a))
Pentamidine	American	Antiprotozoal
(Nebupent)	Pharmaceutical Partners,
	Fujisawa Health Care,
	Inc.
Poly-L-lactic acid	Dermik Laboratories	Dermal Filler
(Sculptra)
Somatropin	Pharmacia Corporation,	Synthetic human growth
	Serono Inc	hormone
Sulfamethoxazole/	Alpha care Inc, Women	Antibacterial
Trimethoprim	First Health Care, King
(Bactrim, Septra)	Pharmaceuticals
(Serostim)
Testosterone	Pfizer Inc, Unimed	Androgens
(Androderm, Androgel,	Pharmaceuticals, Inc.,
Depo-Testosterone)	Alza Corporation,
	Watson Laboratories
Trimetrexate	United States Bioscience	Antiprotozoal
(Neutrexin)	Inc, Medimmune, Inc.

The combinations of the anti-TB compounds of this invention with AIDS antivirals (including anti-HIV integrase-based antivirals), other antivirals, another TB drug and/or a TB drug that is active against drug-resistant TB; immunomodulators, anti-infectives, antibiotics, vaccines, other therapeutic agents are not limited to the list in the above Table, but includes, in principle, any combination with any pharmaceutical composition useful for the treatment against infection by HIV or for treating AIDS or ARC. Preferred combinations are simultaneous or alternating treatments of a compound of the present invention and a protease inhibitor (e.g., indinavir, nelfinavir, ritonavir, saquinavir and others), a reverse transcriptase (RT) inhibitor (e.g., AZT, 3TC, ddC, ddI, d4T, abacavir and others), an integrase inhibitor (e.g., raltegravir, evitegravir) and/or non-nucleoside RT inhibitors (e.g., efavirenz, nevirapine, and others), or some combination of two or more of these inhibitors (see Table above). A few representative examples of relevant patents citing combinations are: EPO 0,484,071, U.S. Pat. No. 5,413,999, WO 9962513.

In such combinations, the compound of the present invention and other active agents may be separately administered or concurrently administered (coadministered). In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).

Rifampin (Rifadin, Rimactane)
Rifapentine
Isoniazid (Nydrazid)
Ethambutol
Ethionamide
Para-aminosalicylic acid (PAS)
Capreomycin
Amikacin
Rifabutin (Mycobutin)
Streptomycin
Pyrazinamide
Cycloserine
Ciprofloxacin
Ofloxacin
Levofloxacin
Clofazimine
Bedaquiline
(−)βDioxolane-G; DXG;
(−)β-Arctigenin; Arctigenin;
(−)-Carbovir; (−)-C-D4G; (−)-Carbovir;
(+13-D-2,6-Diaminopurine dioxolane; Amdoxovir; DAPD; APD
(+)-2′-Deoxy-3′-oxa-4′-thiocytidine; dOTC (+)
(+)-2′-Deoxy-3′-oxa-4′-thio-5-fluorocytidine; dOTFC (+)
(+/−)-Cyclobut-G; A-69992; (+/−)-Lobucavir; C-Oxt-G; Cyclobut-G; C-Oxetanocin-G
(R)-2QuinCOAsnPhe[CHOHCH2]PipCONHtBu
(R)-3,6-Diamino-N-(aminomethyl)hexanamide; Bellenamine
(R)-PMPA; (R)-9-(2-Phosphonylmethoxypropyl)adenine; PMPA-(R); Tenofovir
(R)-PMPDAP; PMPDAP-(R)
(S)-PMPA; (S)-9-(2-Phosphonylmethoxypropyl)adenine; PMPA(S)
(S)-9-(2-Phosphonylmethoxypropyl)adenine; (S)-PMPA
α-APA; R89439; Loviride
α-APA deriv.; R87232
α-APA deriv.; R88703
α-APA enantiomer; R90385
α-L-AZT; AZT-α-L
α-L-DXC; α-L-Dioxalane-C; DXC-α-L-
α-L-FTC; FTC-α-L-
α-Monofluoromethyldehydroornithine methyl ester; MFMOME
1,1′-Azobisformamide; ADA; Azodicarbonamide
1-(11-Octylamino-10-hydroxyundecyl)-3,7-dimethylxanthine; CT-2576
1-(2′,3′-Dideoxy-2′-fluoro-β-D-threo-pentofuranosyl)cytosine; Ro 31-6840
1-(2′-Fluoro-2′,3′-dideoxy-B-D-erythro-pentofuranosyl)thymine; 2′FddT
1-(2OHPr)-4-Substit-piperazine, thienyl carbamate deriv.
1-(2OHPr)-4-Substit-piperazine, thienyl carbamate deriv.
1-(2OHPr)-4-Substit-piperazine, thienyl carbamate deriv.
1-(2OHPr)-4-Substit-piperazine, thienyl carbamate deriv.
1-[(2-Hydroxyethoxy)methyl]-6-(3-methylphenyl)thio)thymine; HEPT-M
1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)-2-thiothymine; HEPT-S
1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)thymine; HEPT
1-Deoxynojirimycin; Deoxynojirimycin
141 W94; VX-478; Amprenavir; Agenerase®; Approved
1592U89 Succinate; Abacavir Succinate; Ziagen® Approved
1-Aminooxyethylamine; AEA
1-Methoxyoxalyl-3,5-dicaffeoylquinic acid; 1-MO-3,5-DCQA; Dicaffeoylquinic acid deriv.
1OH-2(Cbz-Tle)3PhPr[14]paracyclophane deriv.
1OH-2(Cbz-ValNH)3PhPr[13]metacyclophane deriv.
1OH-2(Cbz-ValNH)3PhPr[13]paracyclophane deriv.
1OH-2(Cbz-ValNH)3PhPr[14]paracyclophane deriv.
1OH-2(Cbz-ValNH)3PhPr[17]paracyclophane deriv.
12-Deoxyphorbol-13-(3E,5E-decadienoate); Phorbol deriv.
16.alpha.-Bromoepiandrosterone; Epi-Br; Inactivin; HE 2000; HE2000; PPB2; DHEA deriv.
1-β-D-arabinofuranosyl-5-(2-bromovinyl)uracil; BV-ara-U; BVaraU; BV ara-U; Sorivudine; SQ-32756; Bravavir; Brovavir; Usevir; YN-72; Bromovinyl araU; BVAU
2′,3′-Didehydro-3′-deoxycytidine; D4C
2′,3′-Dideoxydidehydroguanosine; D4G
2′,3′-Didehydro-3′-deoxythymidine; D4T; Stavudine; Zerit® Approved
2′,3′-Dideoxy-3′-fluoro-4-thiothymidine; 3′-F-4-Thio-ddT
2′,3′-Dideoxy-3′-fluoro-5-bromouridine; FddBrU
2′,3′-Dideoxy-3′-fluoro-5-chlorocytidine; 3′-F-5-Cl-ddC
2′,3′-Dideoxy-3′-fluoro-5-chlorouridine; 935U83; 5-Chloro-2′,3′-dideoxy-3′-fluorouridine; FddClU; Raluridine
2′,3′-Dideoxy-5-ethylcytidine; 5-Et-ddC
2′,3′-Dideoxyadenosine; D2A; ddAdo; ddA
2′,3′-Dideoxydidehydroadenosine; d4A
2′,3′-Dideoxyguanosine; D2G; ddG
2′,3′-Dideoxy-3′-hydroxymethyl cytidine; 3′-Hydroxymethyl-ddC; BEA-005
2,5′-Anhydro-3′-azido-2′,3′-dideoxyuridine; AZU-2,5′-anhydro
2,5′-Anhydro-3′-azido-3′-deoxythymidine; AZT-2,5′-anhydro
2′,5′diSilySpiroT; TSAO-T
2′,5′diSilySpiroT; TSAO-me^3T
2,6-Diamino-2′,3′-dideoxypurine-9-ribofuranoside; ddDAPR; DAPDDR; 2,6-Diamino-ddP
2,6-Diaminopurine-2′,3′-dideoxydidehydroriboside; ddeDAPR
2,6-Diaminopurine-3′-fluoro-2′,3′-dideoxyribo side; 3′-F-ddDAPR
2-Aminobenzylstatine Valyl Cbz deriv.; Statine deriv.
2-Glycine amide-5-chlorophenyl 2-pyrryl ketone; GCPK
[2-PyridCH2NCH3CO-Val-NHCH(Bz)]CHOHCHOH; A-77003
2′-Azido-2′,3′-dideoxyadenosine; 9-(2′-Azido-2′,3′-dideoxy-β-D-erythropentofuranosyl)adenine; 2′-N3ddA
2′-FddA(B-D-threo); F-ddA; 2′-F-dd-ara-A; 9-(2′-Fluoro-2′,3′-dideoxy-B-D-threopentafuranosyl)adenine; Lodensine
2′-N3ddA (B-D-threo); 9-(2′-Azido-2′,3′-dideoxy-β-threopentafuranosyl)adenine
2-NaphCOAsnPhe[CHOHCH2]Pro-OtBu
2-Nitrophenylphenylsulfone; NPPS
3-(3-Oxo-1-propenyl)-3′-azido-3′-deoxythymidine; 3-(3-Oxo-1-propenyl)AZT
3-(Phenylsulfonyl)-indole deriv.; L-737,126
3,5-DCQA; 3,5-Dicaffeoylquinic acid; Dicaffeoylquinic acid
3′-Azido-2′,3′-dideoxy-5-[(cyanomethyl)oxy]uridine; 3′-N3-5-Cyanomethyloxy-ddU
3′-Azido-2′,3′-dideoxy-5-aminouridine; 3′-N3-5-NH2-ddU
3′-Azido-2′,3′-dideoxy-5-aza-6-deazauridine; C-analog of 3′-N3-ddU
3′-Azido-2′,3′-dideoxy-5-bromouridine; 3′-N3-5-Br-ddU; AZddBrU
3′-Azido-2′,3′-dideoxy-5-chlorocytidine; 3′-Az-5-Cl-ddC
3′-Azido-2′,3′-dideoxy-5-dimethylaminouridine; 3′-N3-5-NMe2-ddU
3′-Azido-2′,3′-dideoxy-5-ethyluridine; 3′-N3-5-EtddU; CS-85; AZddEtU
3′-Azido-2′,3′-dideoxy-5-fluorocytidine; 3′-N3-5-F-ddC
3′-Azido-2′,3′-dideoxy-5-fluorouridine; AZddFU
3′-Azido-2′,3′-dideoxy-5-hydroxyuridine; 3′-N3-5-OH-ddU
3′-Azido-2′,3′-dideoxy-5-iodouridine; 3′-N3-5-I-ddU; AZddIU
3′-Azido-2′,3′-dideoxy-5-methyaminouridine; 3′-N3-5-NHMe-ddU
3′-Azido-2′,3′-dideoxy-5-methylcytidine; CS-92; 3′-N3-5-Me-ddC
3′-Azido-2′,3′-dideoxy-5-thiocyanatouridine; 3′-N3-5-SCN-ddU
3′-Azido-2′,3′-dideoxy-5-trifluoromethyluridine; 3′-N3-5-CF3-ddU
3′-Azido-2′,3′-dideoxycytidine; CS-91; 3′-N3-ddC
3′-Azido-2′,3′-dideoxyguanosine; AZG; 3′-N3ddG
3′-Azido-2′,3′-dideoxy-N4-5-dimethylcytidine; 3′-N3-N4-5-diMe-ddC
3′-Azido-2′,3′-dideoxy-N4-OH-5-methylcytidine; 3′-N3-N4-OH-5-Me-ddC
3′-Azido-2′,3′-dideoxyuridine; CS-87; 3′-N3ddU; AZdU; Uravidine
3′-Azido-3′-deoxy-6-azathymidine; 3′AZ-6AzaT
3-Azido-3′-deoxythymidilyl-(5′,5′)-2′,3′-dideoxy-5′-adenylic acid; AZT-P-ddA
3′-Azido-3′-deoxythymidilyl-(5′,5′)-2′,3′-dideoxy-5′-adenylic acid, 2-cyanoethyl ester; AZT-P(CyE)-ddA
3′-Azido-3′-deoxythymidilyl-(5′,5′)-2′,3′-dideoxy-5′-inosinic acid; AZT-P-ddI
3′-Azido-3′-deoxythymidine-5′-(butylmethoxyvalinyl)phosphate; 5′MeOValPO3(Bu)AZT
3′-Azido-5-chloro-2′,3′-dideoxyuridine; AzddClUrd; AzddClU
3′-Deoxythymidine; ddT
3′-FddA (B-D-Erythro); 9-(3′-Fluoro-2′,3′-dideoxy-B-D-erythropentafuranosyl)adenine
3′-FddC; 3′-Fluoro-2′,3′-dideoxycytidine
3′-FddG; 3′-Fluoro-2′,3′-dideoxyguanosine
3′-FddT; Alovudine; FddT; FddThD; 3′-FLT; FLT
3′-FddU; 3′-Fluoro-2′,3′-dideoxyuridine
3′-Fluoro-2′,3′-dideoxy-5-iodouridine; FddIU
3′-N3-ddA; 9-(3′-Azido-2′,3′-dideoxy-B-D-erythropentafuranosyl)adenine
3TC; Lamivudine; Epivir® Approved;
Lamivudine & Zidovudine; Combivir® 3TC & AZT; Approved
4′-Acetoamidophenyl4-guadinobenzoate; AGB
4′-Az-3′-dT; 4′-Azido-3′-deoxythymidine
4′-Az-5CldU; 4′-Azido-5-chloro-2′-deoxyuridine
4′-AzdA; 4′-Azido-2′-deoxyadenosine
4′-AzdC; 4′-Azido-2′-deoxycytidine
4′-AzdG; 4′-Azido-2′-deoxyguanosine
4′-AzdI; 4′-Azido-2′-deoxyinosine
4′-AzdU; 4′-Azido-2′-deoxyuridine
4′-Azido-2′-deoxy-β-D-erythro-pentofuranosyl-5-methyl-2,4-dioxopyrimidine; 4′-Azidothymidine
4′-Cyanothymidine; 4′-CN-T
4-Methyl-5-(pyrazinyl)-3H-1,2-dithiole-3-thione; Oltipraz
5′-[(1,4-Dihydro-1-methyl-3-pyridinylcarbonyl)oxy]-3′-azido-2′,3′-deoxythymidine; DP-AZT; HP-AZT; AZT Prodrug; AZT-DHP
5′-[[(Z)-4-amino-2-butenyl]methylamino]-5′-deoxyadenosine; MDL 73811
5′-Alkylglycosidecarbonate of 3′-azido-3′-deoxythymidine; AcNHGlc-hexyl-CO3 AZT
5Cl3PhS-2IndolCONH2
5-Fluoro-2′,3′-dideoxycytidine; 5-F-ddC
5-Methyl-3′-azido-2′,3′-dideoxyisocytidine; MeAZddIsoC
6-O-Butanoylcastanospermine; BuCast; MDL 28,574; Celgosivir
6-Chloro-9-(2,3-dideoxy-b-D-glyceropentofuranosyl)-9H-purine; D2ClP; 6-Chloro-ddP; CPDDR; 6Cl-ddP
6-Dimethylaminopurine-2′,3′-dideoxyriboside; N-6-dimethylddA; DMAPDDR
7-Chloro-N-methyl-5-(1H-pyrrol-2-yl)-3H-1,4-benzodiazepin-2-amine; Ro 24-7429
7-Chloro-5-(2-pyrryl)-3H-1,4-benzodiazepin-2(H)-one; Ro 5-3335
8-Chloro-TIBO; Tivirapine; R86183
9-(2,3-Dideoxy-β-D-ribofuranosyl)-6-(methylthio)purine; D2SMeP
9-[Bis(OHMe)cBu]A; A-69463; Cyclobutyl-A; Cyclobut-A; C-oxetanocin A
A-76890
A-77212
A-80987; Ritonavir deriv., A-81525; Ritonavir deriv., A-83962; Ritonavir deriv.
A-98881; Azacyclic urea deriv.
AA; L-ascorbic acid; Calcium Ascorbate
AAP-BHAP; U-104489; PNU-104489
Abacavir & Lamivudine & Zidovudine; Trizivir® ABC & (−)-3TC & AZT
ABT-378; Lopinavir; Component of Kaletra; Aluviran®
ABT-378 & ABT-538; Kaletra®; Lopinavir & Ritonavir; Aluviran® & Norvir®
ABT-538; Norvir®; Ritonavir; Component of Kaletra; Approved
Acemannan
Adefovir; PMEA; GS-0393
Adefovir dipivoxil; BisPom PMEA; GS-840; Preveon®
AG-1343; Viracept®; Nelfinavir; Approved
AG1350; LY316957; Nelfinavir-octahydro-thienopyridine analog
AHPBA analog; R-87366
Alpha-lipoic acid; α-Lipoic acid; Thioctic acid
ALX40-4C
AMD3100; JM3100
Amprenavir phosphate; VX-175; GW433908; GW433908A (*Sodium Salt*); GW433908G (*Calcium Salt*); Fosamprenavir
Ancer 20; Z-100
Anti-sense 25-mer phosphorothioate; GEM91
Atazanavir; CGP-73547; BMS-232632; BMS 232632; Zrivada; Latazanavir; Reyataz®
Atevirdine; U-87201E; BHAP deriv.
Aurintricarboxylic acid; Dupont ATA; Dupont DA639; SD-095345; ATA
AY 9944; trans-1,4-Bis(2-dichlorobenzylaminoethyl)cyclohexane dichlorhydrate
AZT; Zidovudine; Azidothymidine; Retrovir®
AZT-PO3(CH3)-AZT; O,O′-Bis(3′-azido-3′-deoxythymidin-5′-yl)methylphosphonate
Baicalin; TJN-151
Betulinic acid; Mairin
Betulinic acid, 3-O-(3′,3′-dimethylsuccinate)
BHAP deriv.
BHAP deriv.; Rescriptor®; Delavirdine; U-90152
BHAP deriv.; U-88204E
BI-RG-587; Nevirapine; Viramune® Approved
BILA 1906 BS, BILA 2011 BS; Palinavir, BILA 2185 BS
Bis(2-nitrophenyl)sulfone; Bis(2NO2Ph)SO2; NSC633001
bis-ValHOEt-N2aza-peptide isostere; CGP 53820
bis-ValHOEt-N2aza-peptide isostere; CGP 53820 analog
BMS-186318
BocPhe[CHOH(CH2)3CH═CHPhCO]IleAMBI; L-687,908
BzOCValPhe[diCHOH(RR)]PheValBzOC
BzOCValPhe[diCHOH(SS)]PheValBzOC
C2-Sym Phosphinic amide deriv. (HOECHST AG)
Calanolide A; NSC675451, Calanolide B
Capravirine; S-1153
Castanospermine
CbzAF(CHOHCH2)AVVOMe
Cbz-Asn-Apns-Pro-NH-tBu; KNI-102
CGP 61755; Lasinavir, CGP 64222
CNI-H0294
Coactinon; I-EBU; HEPT deriv.; MKC-442; Emivirine
Conocurvone; NSC650891
Coviracil; (−)FTC; (−)-2′,3′-Dideoxy-5-fluoro-3′-thiacytidine; Emtricitabine; Emtriva
C-Oxetanocin-G; A-69992; (+−)Lobucavir; C-Oxt-G; Cyclobut-G; (+−)Cyclobut-G
Crixivan®; Indinavir; MK639; L-735,524; Approved
Curdlan Sulfate
CV-N; Cyanovirin-N
Cyclic Urea Amide; SD 146
Cyclosporin A; Sandimmune®
[Me-Ile-4]Cyclosporin A; SDZ NIM 811
D4A (L); L-2′,3′-Didehydro-2′,3′-dideoxyadenosine
D4FC; D-D4FC; 2′,3′-Didehydro-2′,3′-dideoxy-5-fluorocytidine; DPC 817
D4FC (L); L-2′,3′-Didehydro-2′,3′-dideoxy-5-fluorocytidine
D4G (L); L-2′,3′-Didehydro-2′,3′-dideoxyguanosine
D4I (L); L-2′,3′-Didehydro-2′,3′-dideoxyinosine
DABO
ddC; Dideoxycytidine; Zalcitabine; Hivid®
ddI; Dideoxyinosine; Didanosine; Videx®
Dehydroepiandrosterone; DHEA; Prasterone; Dehydroisoandrosterone; EL-10
Dextran Sulfate
Dicaffeic acid ester; L-Chicoric acid
DMP-266; Sustiva®; Efavirenz; Approved
DMP-323; XM-323
DMP-450
Docosanol; n-Docosanol
dOTC (−); (−)-2′-Deoxy-3′-oxa-4′-thiocytidine
dOTFC (−); (−)-2′-Deoxy-3′-oxa-4′-thio-5-fluorocytidine
DP-178; Pentafuside; T-20; GP41 127-162 AA; Enfuvirtide; Fuzeon®
E-BPTU; HEPT deriv.; NSC 648400
E-EBU; HEPT deriv.; MKC-442 deriv.
E-EBU-dM; HEPT deriv.; MKC-442 deriv.
E-EPSeU; HEPT deriv.; MKC-442 deriv.
E-EPU; HEPT deriv.; MKC-442 deriv.
Ebselen
Etoposide
Epoxy steriod deriv.; (4α,5α,17β)-17-Hydroxy-3-oxo-4,5-epoxyandrostane-2-carboxamide
Eulicin
Fenalamide A1; Phenalamide A1; Stipiamide
Fleephilone
Fluoroquinolone deriv.; K-12
Fortovase®; Invirase®; Saquinavir; Ro31-8959; Approved
Foscarnet; Phosphonoformic acid; Foscavir;
FPMDAP, FPMPA, FPMPG
GPGRAF Octomer; SPC3
Hammerhead anti-gag RNA Ribozyme B
Harziphilone
HBY 097; Quinoxaline deriv.
HEPT deriv.; MKC-442 deriv.
HOCH2CH2 isostere; ThienopyridCON thienyl urethane deriv.
HOCH2CH2 isostere; ThienopyridCONthienyl urethane deriv.; LY326188
HPMPA
HPMPDAP
HU; Hydroxyurea; Hydrea
Hydroxocobalamin
Hypericin
Ingenol 3,5,20-triacetate; ITA; RD3-2118
Ingenol deriv.; RD4-2138
Inophyllum B, Inophyllum P
iQoa-Mta-Apns-Thz-NH-tBu; KNI-272
Isentress (Raltegravir)
IsoquinCON furanyl urethane analog
IsoquinCON thienyl urethane analog
KNI-154; Noa-Asn-Apns-Thz-NH-tBu, KNI-174; Noa-Asn-Apns-Dmt-NH-tBu
KNI-227; Qoa-Mta-Apns-Thz-NH-tBu
L-685,434, L-685,434-6-Hydroxy derivative, L-685,434-OEtMorphderivative; L-689,502
L-685,434-OEtNMe2, L-685,434-OPrMorph derivative, L-697,593; 2-Pyridinone deriv.
L-697,639; 2-Pyridinone deriv., L-697,661; 2-Pyridinone deriv.
L-FddC; β-L-5F-ddC
Lamivudine & Zidovudine; Combivir® 3TC & AZT; Approved
LY289612, LY289612 analog, LY289612 analog
LY-300046-HCl; PETT deriv.; Trovirdine
LY314163; Saquinavir/Nelfinavir deriv.
LY-73497; N-(2-Phenethyl)-N′-(2-thiazolyl)thiourea; PETT
MAP; Methyl acetylenic putrescine
Michellamine A; NSC650898, Michellamine B; NSC649324, Michellamine F
N-6-Et-ddA; N-Ethyl-2′,3′-dideoxyadenosine
N-6-methyl ddA; N6-Methyl-2′,3′-dideoxyadenosine
Naphthalene 2-sulphonate polymer; PRO 2000
Nelfinavir-octahydro-thienopyridine analog
Nonoxynol 9
NSC625487; Thiazolobenzimidazole; TBZ
Oxathiin deriv.; UC-38, Oxathiin deriv.; UC-84
P9941
Penicillin Et(NH)2 Sym dimer, Penicillin G, ET(NH)2 deriv.
Penicillin, 2Isoquin-OHPrNH2 analog
Pentosan Sulfate; Elmiron; SP54; Xylan Sulfate;
PETT Cl, F deriv., PETT deriv.
Phenoxan
Phorbol deriv.; Prostratin
Platanic acid
PMEDAP, PMEG, PMEHx; PMEI, PMEMAP, PMET
PNU-140690; U-140690; Tipranavir
Pyridinone deriv.
Quinoxalin2thione deriv; S-2720
R14458; TIBO deriv.
R82150; TIBO deriv.
R82913; TIBO deriv.
Resobene
Ribavirin; Virazole
Ro 31-8959-bis-thf deriv.
Saquinavir/Nelfinavir deriv.
SB-205569; Val-Phe-Phe-HOCH2CH2 isostere analog
SC-52151; Telinavir
SDZ PRI 053
Suramin Sodium
T22
Thalidomide
Thiangazole; (−)-Thiangazole, Thiazoloisoindol-5-one, Thiazoloisoindol-5-one, deriv.
Tle-Val-Sta, 5PhBuCOOH deriv.; Statine deriv.
UC-781
Val-Val-Sta, 5PhBuCOOH deriv.; Statine deriv.
VB-11,328
Viread®; Tenofovir Disoproxil

An alternative list of drugs and/or bioactive agents useful in the treatment of TB infections, or conditions or disease states which are secondary to TB infections is set forth herein below. One or more of these agents may be used in combination (coadministered) with at least one anti-MDR TB agent as otherwise disclosed herein to treat MDR-TB or other drug-resistant TB and co-infections with other conditions or disease states, including AIDS/ARC, Kaposi's sarcoma, hepatitis B and C virus infections, and other microbial infections. When used, these compounds are also included in effective amounts.

These list of drugs and/or bioactive agents include those at the following website: aidsinfo.nih.gov/DrugsNew/DrugDetailNT.aspx?MenuItem=Drugs&Search=On&int_id=257 FDA Approved: Tuberculosis Rifampin (Rifadin, Rimactane); Rifapentine; Isoniazid (Nydrazid); Ethambutol; Ethambutol Hydrochloride; Ethionamide; Para-aminosalicylic acid (PAS); Capreomycin; Amikacin; Rifabutin (Mycobutin); Streptomycin; Pyrazinamide; Cycloserine; Ciprofloxacin; Ofloxacin; Levofloxacin; Clofazimine; Bedaquiline; Moxifloxacin Hydrochloride; HIV Combination Drugs Atripla; Combivir; Complera; Epzicom; Kaletra; Stribild; Trizivir; Truvada; Entry and Fusion Inhibitors Enfuvirtide; Maraviroc; Integrase Inhibitors Raltegravir; Non-nucleoside Reverse Transcriptase Inhibitors Delavirdine; Efavirenz; Etravirine; Nevirapine; Rilpivirine Nucleoside Reverse Transcriptase Inhibitors Abacavir; Abacavir/Lamivudine; Abacavir/Lamivudine/Zidovudine; Didanosine; Emtricitabine; Emtricitabine/Tenofovir Disoproxil Fumarate; Lamivudine; Lamivudine/Zidovudine; Stavudine; Tenofovir Disoproxil Fumarate; Zidovudine Protease Inhibitors Atazanavir; Darunavir; Fosamprenavir; Indinavir; Lopinavir/Ritonavir; Nelfinavir; Ritonavir; Saquinavir; Tipranavir. Opportunistic Infections Aspergillosis; Amphotericin B; Voriconazole; Coccidioidomycosis; Amphotericin B; Fluconazole; Itraconazole; Cryptococcosis; Amphotericin B; Fluconazole; Flucytosine; Itraconazole; Cryptosporidiosis/Microsporidiosis Albendazole; Itraconazole; Cytomegalovirus Disease Foscarnet Sodium; GanciClovir; Valganciclovir Hydrochloride; Disseminated Mycobacterium avium Complex Disease Azithromycin; Ciprofloxacin; Clarithromycin; Ethambutol Hydrochloride; Levofloxacin; Moxifloxacin Hydrochloride; Rifabutin; Hepatitis B Virus Infection Hepatitis B Vaccine; Peginterferon Alfa-2a; Hepatitis C Virus Infection Peginterferon Alfa-2a; Peginterferon Alfa-2b; Ribavirin; Herpes Simplex Virus Disease Acyclovir; Famciclovir; Foscarnet Sodium; Imiquimod; Valacyclovir Hydrochloride; Histoplasmosis Amphotericin B; Itraconazole; Human Herpesvirus-8 Diseases Ganciclovir; Valganciclovir Hydrochloride; Isosporiasis Ciprofloxacin; Pyrimethamine; Sulfamethoxazole/Trimethoprim; Leishmaniasis Amphotericin B; Mucocutaneous Candidiasis Amphotericin B; Butoconazole Nitrate; Clotrimazole; Fluconazole; Itraconazole; Miconazole; Terconazole; Voriconazole; Penicilliosis marneffei Amphotericin B; Itraconazole; Pneumocystis; Pneumonia Clindamycin; Primaquine Phosphate; PyrimethamineiSulfamethoxazole/Trimethoprim; Toxoplasma gondii Encephalitis Azithromycin; Clindamycin; Pyrimethamine; Sulfadiazine; Sulfamethoxazole/Trimethoprim; Varicella-Zoster Virus Diseases Acyclovir; Famciclovir; Foscarnet Sodium; Ganciclovir; Valacyclovir Hydrochloride; Varicella Virus Vaccine Live

Investigational: HIV Entry and Fusion Inhibitors AMD-070; BMS-663068; Cenicriviroc; INCB-9471; Ibalizumab; PRO-140: Integrase Inhibitors Dolutegravir; S/GSK1265744; Non-nucleoside Reverse Transcriptase Inhibitors Lersivirine; Nucleoside Reverse Transcriptase Inhibitors BMS-986001; Elvucitabine; GS-7340; Racivir.
Chemical Synthesis: General Synthetic Scheme

A general scheme for the synthesis is shown below in Scheme 1. The precursors to the target molecules are indicated. These precursors were synthesized by modifications of methodologies developed in the Nair laboratory [J. Org. Chem. 72, 8577-8579 (2007); ACS Med. Chem. Lett. 2, 877-881 (2011); J. Med. Chem. 49, 445447 (2006); J. Am. Chem. Soc. 109, 7223-7224 (1987); J. Org. Chem. 53, 30513057 (1988)]. The key and most important step in the synthesis is the conversion of these precursors to the target molecules and the methodologies for these conversions are indicated.

CHEMICAL SYNTHESIS: REPRESENTATIVE EXAMPLES

The following representative examples are provided to illustrate details for the preparation of the compounds of the present invention. The examples are not intended to be limitations on the scope of the present invention and they should not be so construed. Furthermore, the compounds described in the following examples are not to be viewed as forming the only set of compounds that is considered as the invention, and any combination of components of the compounds or their moieties may itself form a set. This has been addressed previously in this patent document. Those skilled in the art will readily comprehend that known variations of reaction conditions and synthetic conversions described in the following preparative procedures can be used to readily prepare these other compounds routinely.

Representative Example 1 4-(1-(2-Fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione (2)

To a chilled solution of 4-(1-(2-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-2-oxobut-3-enoic acid 1, prepared using modifications of methodologies previously described by us, J. Org. Chem. 72, 8577-8579 (2007); ACS Med. Chem. Lett. 2, 877-881 (2011), (103 mg, 0.224 mmol) in dimethylformamide (DMF) (1.3 mL) was added hydroxybenzotriazole (HOBT) (33 mg, 0.246 mmol), followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI-HCl) (47 mg, 0.246 mmol). The mixture was stirred at 0° C. for 20 minutes and then 4-(naphthalen-1-yl)piperazin-1-ium chloride 3, (61 mg, 0.2463 mmol) and NaHCO₃(21 mg, 0.246 mmol) were added. Stirring was continued for 2.5 h at 0° C. Water was then added to precipitate the product, which was filtered and washed with additional water. This solid was dissolved in ethyl acetate (50 mL) and the solution washed with water (4×50 mL) The ethyl acetate extract was concentrated in vacuo and the resulting oily product was dried in vacuo to give the crude product, which was passed through a short silica gel column with chloroform as the eluting solvent. The eluent was removed and the residue was triturated with pentane to give a yellow amorphous powder (44.1 mg, 30%). UV (methanol): λ 387 nm (ε 16,349); 305 nm (ε 10,899). ¹H-NMR (DMSO-d₆, 500 MHz), δ 15.00 (bs, 1H), 8.21-8.12 (m, 3H), 7.95-7.91 (m, 1H), 7.68-7.00 (m, 12H), 5.25 (bs, 214), 3.88-3.74 (m, 6H), 3.74-2.82 (m, 4H). HRMS: calculated mass 656.2172 for C₃₇H₃₀F₄N₃O₄[M+H]⁺; found 656.2170.

Representative Example 2 4-(1,5-Dibenzyl-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione (4)

The title compound 4 was synthesized using the procedure described above for compound 2 using 4-(1,5-dibenzyl-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxy-2-oxobut-3-enoic acid as the precursor. The product was isolated as a yellow solid. UV (methanol): λ 390 nm (ε 15,333), 302 nm (ε 10,810). ¹H-NMR (DMSO-d₆, 500 MHz), δ 15.04 (bs, 1H), 8.34 (bs, 8.19 (m, 114), 7.91 (m, 1H), 7.65 (m, 1H), 7.55-7.16 (m, 16H), 5.23 (s, 2H), 3.86-3.73 (m, 6H), 3.04 (m, 4H).

HRMS: calculated mass 584.2549 for C₃₇H₃₄N₃O₄[M+H]⁺; found 584.2543.

Representative Example 3 1-(4-([1,1′-Biphenyl]-4-yl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione (5)

To a chilled solution of 4-(1-(2-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-2-oxobut-3-enoic acid 1, (100 mg, 0.217 mmol) in DMF (1.3 mL) was added hydroxybenzotriazole (HOBT) (32 mg, 0.238 mmol), followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI-HCl) (46 mg, 0.238 mmol). The mixture was stirred for 30 minutes, treated with 1-([1,1′-biphenyl]-4-yl)piperazine 6, (57 mg, 0.238 mmol) and the resulting reaction mixture was stirred for 2.5 h at 0° C. Water was then added to precipitate the product, which was filtered and washed with additional water. This solid was dissolved in ethyl acetate (50 mL) and the solution washed with water (4×50 mL) and finally with brine (100 mL). The ethyl acetate extract was concentrated in vacuo and the resulting oily product was dried in vacuo to give the crude product, which was passed through a short silica gel column with chloroform as the eluting solvent. The eluent was removed and the residue was triturated with pentane to give a yellow amorphous powder (83 mg, 56%). UV (methanol): λ 389 nm (ε 16,746), λ 284 nm (ε 27,712). ¹H-NMR (CDCl₃, 500 MHz), δ 15.15 (bs, 1H), 8.24 (m, 1H), 7.60-7.03 (m, 19H), 6.74 (t, 2H), 5.20 (bs, 2H), 3.88-3.86 (m, 2H), 3.80 (s, 2H), 3.78-3.75 (m, 2H), 3.34-3.21 (m, 4H). HRMS: calculated mass 682.2329 for C₃₉H₃₂F₄N₃O₄[M+H]⁺; found 682.2326.

Representative Example 4 1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-2-ene-1,4-dione (7)

The title compound 7 was synthesized by the procedure described above for compound 5 using appropriate precursors. The product was a yellow solid. UV (methanol): λ 389 nm (ε 15,521), 266 nm (ε 23,131). ¹H-NMR (CDCl₃, 500 MHz): δ 8.19-8.20 (m, 1H), 7.79 (s, 1H), 7.50-7.57 (m, 2H), 7.42-7.45 (m, 1H), 7.28-7.33 (m, 3H), 7.19-7.23 (m, 2H), 7.06-7.14 (m, 2H), 6.94-6.99 (m, 2H), 6.69 (t, 2H, J=8.0 Hz), 5.16 (s, 2H), 3.71-3.83 (m, 6H), 3.16-3.28 (m, 4H), 1.25 (s, 1H). HRMS: calculated for C₃₆H₃₀F₄N₅O₄[M+H]⁺672.2234, found 672.2241.

Representative Example 5 1-(4-([1,1′-Biphenyl]-3-yl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl) 1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione (8)

The title compound was synthesized by the procedure described above for compound 5 using appropriate precursors. The product was a yellow powder. UV (methanol): λ 388 nm (ε 13,958), 307 nm (ε 5,696), 241 nm (ε 35,609). ¹H-NMR (CDCl₃, 500 MHz), δ 8.14 (bs, 1H), 7.51-7.19 (m, 10H), 7.08-7.00 (m, 4H), 6.86 (d, 1H), 6.65-6.61 (m, 2H), 5.08 (bs, 21-1), 3.77-3.67 (m, 6H), 3.23-3.12 (m, 411). HRMS: calculated mass 682.2329 for C₃₉H₃₂F₄N₃O₄[M+H]⁺; found 682.2326.

Representative Example 6 1-(4-(4-(Dimethylamino)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione (9)

The title compound 9 was synthesized by the procedure described above for compound 5 using appropriate precursors. The product was a dark yellow solid. UV (methanol): λ 387 nm (ε 12,272), 315 nm (ε 5,766), 261 nm (ε 17,968). ¹H-NMR (DMSO, 500 MHz): δ 8.20 (s, 1H), 8.14-8.05 (m, 1H), 7.38-7.18 (m, 7H), 6.88-6.69 (m, 4H), 5.25 (s, 2H), 3.88 (s, 2H), 3.67-3.47 (m, 4H), 3.35 (bs, 2H), 3.01-2.95 (m, 3H), 2.82-2.78 (m, 6H). HRMS: calculated mass 649.2438 for C₃₅H₃₃F₄N₄O₄[M+H]⁺; found 649.2414.

Representative Example 7 1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1,5-dibenzyl-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione (10)

The title compound 10 was synthesized by the procedure described above for compound 5 using appropriate precursors. The product was a yellow solid. UV (methanol): λ 390 nm (ε 18,858), 266 nm (ε 29,129). ¹H-NMR (CDCl₃, 500 MHz): δ 8.11, 8.13 (dd, 1H, J=2.5 Hz), 7.70 (s, 1H), 7.48 (s, 1H), 7.04-7.29 (m, 14H), 6.91 (d, 2H, J=8.5 Hz), 6.82 (d, 11-1, J=8.5 Hz), 5.07 (s, 2H), 3.59-3.76 (m, 6H), 2.95-3.20 (m, 4H). HRMS: Calculated for C₃₆H₃₄N₅O₄[M+H]⁺600.2611, found 600.2612.

Representative Example 8 1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione (11)

The title compound 11 was synthesized by the procedure described above for compound 5 using appropriate precursors. The product was a yellow solid. UV (methanol): λ 373 nm (ε 12,483), 269 nm (ε 28,993). ¹H-NMR (CDCl₃, 500 MHz): δ 8.18, 8.20 (dd, 1H, J=3.0, 2.5 Hz), 7.50-7.55 (m, 2H), 7.44 (t, 1H, J=7.75 Hz), 7.29-7.33 (m, 4H), 6.92-7.14 (m, 6H), 6.66-6.71 (m, 2H), 6.31 (s, 2H), 5.16 (s, 2H), 3.70-3.83 (m, 6H), 3.12-3.24 (m, 4H). HRMS: calculated mass for C₃₇H₃₁F₄N₄O₄[M+H]⁺671.2281; found 671.2259.

Representative Example 9 1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1,5-dibenzyl-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione (12)

The title compound 12 was synthesized by the procedure described above for compound 5 using appropriate precursors. The product was a yellow solid. UV (methanol): λ 368 nm (ε 13,413), 271 nm (ε 29,880). ¹H-NMR (CDCl₃, 500 MHz): δ 8.18, 8.21 (dd, 1H, J=3.0 Hz), 7.55 (s, 1H), 7.24-7.36 (m, 13H), 7.11-7.14 (m, 2H), 6.96-7.01 (m, 2H), 6.88 (d, 1H, J=8.0 Hz), 6.31 (t, 2H, J=2.0 Hz), 5.14 (s, 2H), 3.68-3.83 (m, 6H), 3.19-3.24 (m, 4H). HRMS: calculated mass 599.2658 for C₃₇H₃₅N₄O₄[M+H]⁺; found 599.2640.

Representative Example 10 1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(5-(3,5-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione(13)

The title compound 13 was synthesized by the procedure described above for compound 5 using appropriate precursors. The product was a yellow solid. UV (methanol): 376 nm (ε 15,065), 269 nm (ε 31,601). ¹H-NMR (CDCl₃, 500 MHz): δ 8.15 (d, 1H, J=2.5 Hz), 7.58 (s, 1H), 7.50-7.55 (m, 2H), 7.32-7.36 (m, 3H), 7.10-7.20 (m, 2H), 7.00-7.05 (m, 4H), 6.68-6.78 (m, 3H), 6.36 (t, 2H, J=1.75 Hz), 5.22 (s, 2H), 3.88 (bs, 2H), 3.80 (s, 2H), 3.77 (bs, 2H), 3.25-3.29 (m, 4H). HRMS: calculated mass 653.2376 for C₃₇H₃₂F₃N₄O₄[M+H]⁺; found 653.2357.

Representative Example 11 1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(5-(2,6-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione (14)

The title compound 14 was synthesized by the procedure described above for compound 5 using appropriate precursors. The product was a yellow solid. UV (methanol): λ 388 nm (ε 15,140), 269 nm (ε 25,878). ¹H-NMR (CDCl₃, 500 MHz) δ 8.24 (s, 111), 7.52-7.15 (m, 7H), 7.13-6.89 (m, 8H), 6.32 (s, 2H), 5.16-5.15 (m, 2H), 4.44 (s, 0.3H), 3.81-3.72 (m, 6H), 3.23-3.20 (m, 4H). HRMS: calculated mass 653.2376 for C₃₇H₃₂F₃N₄O₄[M+H]⁺; found 653.2360.

Representative Example 12 1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-5-(4-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione (15)

The title compound 15 was synthesized by the procedure described above for compound 5 using appropriate precursors. The product was a yellow solid. UV (methanol): λ 390 nm (ε 14,942), 269 nm (ε 25,779). ¹H-NMR (CDCl₃, 500 MHz): δ 3.12-3.25 (m, 4H), 3.71-3.91 (m, 711), 4.47 (s, 0.3H), 5.14-5.16 (m, 2H), 6.32-6.33 (m, 2H), 6.93-7.15 (m, 1011), 7.15-7.52 (m, 7H), 8.13-8.14 (m, 1H). HRMS: calculated mass 635.2470 for C₃₇H₃₃F₂N₄O₄[M+H]⁺; found 653.2451.

Representative Example 13 4-(1-(2-Fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione (16)

The title compound 16 was synthesized by the procedure described above for compound 2 using appropriate precursors. The product was a yellow solid. UV (methanol): λ 385 nm (ε 12,721), 247 nm (ε 11,768). ¹H-NMR (CDCl₃, 500 MHz): δ=15.10-15.12 (m, 0.5H), 8.18-8.20 (m, 1H), 7.44-7.57 (m, 2H), 7.24-7.33 (m, 4H), 7.06-7.14 (m, 2H), 6.90-6.94 (m, 3H), 6.66-6.71 (m, 2H), 5.14-5.15 (m, 2H), 3.69-3.82 (m, 6H), 3.12-3.24 (m, 4H). HRMS: calculated mass 606.2016 for C₃₃H₂₈F₄N₃O₄[M+H]⁺; found 606.2012.

Biology

Method for Agar Dilution Drug Susceptibility Assays Against Multidrug-Resistant Mycobacterium Tuberculosis (MDR-TB)

The following assays were conducted against MDR-TB following the screening guidelines of the Clinical and Laboratory Standards Institute (CLSI).

Materials.

The compounds were stable at room temperature and were stored at room temperature until the day of the drug susceptibility assay. Prior to screening, the compounds were solubilized in a minimum amount of DMSO. The screening was done with an isolate of MDR-TB that was resistant to both isoniazid (INH) and rifampin (R). This isolate used for the screening assays was an aliquot from a working stock culture collection that had been stored frozen at −80° C. The aliquot was allowed to thaw at room temperature and subsequently diluted in test media. The screening assays used the following positive and negative controls: (a) organism only (negative control); (b) streptomycin (anti-MDR-TB drug, positive control).

Methods.

The agar dilution susceptibility assay method and format were utilized for susceptibility testing. The agar medium, Middlebrook 7H10 (BD BioSciences; Sparks, Md.), was prepared according to the manufacturer's guidelines and the test compounds were serially diluted two-fold to achieve a testing concentration range from 25 micrograms/mL to 0.012 micrograms/mL (total of 12 concentrations). Each concentration of compound was mixed with Middlebrook 7H10 agar, poured into sterile petri dishes (plates) and allowed to solidify. The plates were subsequently inoculated with approximately 2.0×10³CFU M. tuberculosis and incubated for 21 days at 37° C. Testing was conducted in triplicate and the MICs (minimum inhibitory concentrations) were reported as the lowest concentration (micrograms/mL) of drug that completely inhibited growth of the organism as visibly determined.

Activity.

Anti-MDR TB activities were observed for a significant number of compounds of this invention. The X substitutions were aromatic groups and also those in which the X aromatic group was additionally substituted with heterocyclic rings. The more active compounds had MICs against MDR-TB that were either less than one microgram/mL or significantly less than one microgram/mL.

Claims

We claim:

1. A compound according to Formula I, including tautomers, geometric isomers and pharmaceutically acceptable salts thereof

wherein R₁, R₂, R₃and R₄are each independently H or F; and

X is a phenyl group which is optionally substituted with dimethylamine or a nitrogen containing heterocyclic group selected from the group consisting of pyrrolyl, imidazolyl, pyrazolyl and triazolyl, or X is a biphenyl, naphthyl, anthracenyl or phenanthryl group.

2. A compound according to claim 1 wherein

R₁=H, R₂=H, R₃=H, R₄=H;

R₁=H, R₂=o-F, R₃=o-F, R₄=p-F;

R₁=o-F, R₂=o-F, R₃=o-F, R₄=m-F;

R₁=o-F, R₂=o-F, R₃=o-F, R₄=p-F

R₁=o-F, R₂=o-F, R₃=m-F, R₄=m-F;

R₁=o-F, R₂=o-F, R₃=m-F, R₄=p-F

R₁=o-F, R₂=m-F, R₃=m-F, R₄=p-F;

R₁=H, R₂=m-F, R₃=m-F, R₄=p-F;

R₁=m-F, R₂=o-F, R₃=o-F, R₄=m-F;

R₁=m-F, R₂=o-F, R₃=o-F, R₄=p-F;

R₁=m-F, R₂=o-F, R₃=m-F, R₄=m-F;

R₁=m-F, R₂=o-F, R₃=m-F, R₄=p-F;

R₁=m-F, R₂=o-F, R₃=m-F, R₄=p-F

R₁=H, R₂=o-F, R₃=o-F, R₄=m-F;

R₁=p-F, R₂=o-F, R₃=o-F, R₄=m-F;

R₁=p-F, R₂=o-F, R₃=o-F, R₄=p-F;

R₁=p-F, R₂=o-F, R₃=m-F, R₄=m-F;

R₁=p-F, R₂=o-F, R₃=m-F, R₄=p-F;

R₁=p-F, R₂=m-F, R₃=m-F, R₄=p-F;

R₁=o-F, R₂=m-F, R₃=m-F, R₄=H;

R₁=o-F, R₂=p-F, R₃=H, R₄=H or

R₁=o-F, R₂=o-F, R₃=o-F, R₄=H.

3. A compound according to claim 1 wherein X is

4. A compound according to claim 1 wherein X is a phenyl group or a naphthyl, anthracenyl or phenanthryl group.

5. The compound according to claim 1 wherein X is a phenyl group which is substituted with a dimethylamine or a nitrogen-containing heterocyclic group selected from the group consisting of pyrrolyl, imidazolyl, pyrazolyl and triazolyl and wherein said pyrrolyl group is a 1H-pyrrol-1-yl group, said imidazolyl group is a 1H-imidazol-1-yl group, said pyrazolyl group is a 1H-pyrazol-1-yl group and said triazolyl group is a 1H-1,2,4-triazolyl group.

6. The compound according to claim 5 wherein said nitrogen-containing heterocyclic group is selected from the group consisting of 1H-pyrrol-1-yl group, a 1H-imidazol-1-yl group and a 1H-pyrazol-1-yl group.

7. The compound according to claim 5 wherein said nitrogen-containing group is a 1H-1,2,4-triazolyl group.

8. The compound according to claim 1 which is:

4-(1,5-dibenzyl-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione;

1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1,5-dibenzyl-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

4-(1,5-dibenzyl-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione;

4-(1,5-dibenzyl-2-oxo-1,2-dihydropyridin-3-yl)-1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1,5-dibenzyl-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1,5-dibenzyl-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1,5-dibenzyl-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1,5-dibenzyl-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

4-(1-(2-fluorobenzyl)-5-(4-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione;

1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-5-(4-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

4-(1-(2-fluorobenzyl)-5-(4-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione;

1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-5-(4-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-5-(4-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-5-(4-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-5-(4-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-5-(4-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

4-(5-(2,6-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione;

4-(5-(2,6-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione;

1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(5-(2,6-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

4-(5-(2,6-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(5-(2,6-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(5-(2,6-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(5-(2,6-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(5-(2,6-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

4-(5-(3,5-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione;

1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(5-(3,5-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

4-(5-(3,5-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione;

1-(4-(5-(3,5-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(5-(3,5-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(5-(3,5-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(5-(3,5-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(5-(3,5-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

4-(1-benzyl-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione;

1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1-benzyl-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

4-(1-benzyl-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione;

4-(1-benzyl-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-benzyl-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-benzyl-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1-benzyl-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-benzyl-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

4-(1-(2-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione;

1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

4-(1-(2-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione;

1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

4-(1-(4-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione;

1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1-(4-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

4-(1-(4-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione;

1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-(1-(4-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-(4-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(4-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(4-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione; or

1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(4-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione.

9. The compound according to claim 1 which is:

4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione;

1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione;

1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione;

1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione;

1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione;

1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione;

1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

4-(1-(2-fluorobenzyl)-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione; or

1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione.

10. The compound according to claim 1 which is:

4-(1-(2-fluorobenzyl)-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione;

1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

4-(1-benzyl-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione;

1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1-benzyl-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

4-(1-benzyl-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione;

4-(1-benzyl-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-benzyl-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-benzyl-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1-benzyl-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-benzyl-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione;

1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalene-1-yl)piperazin-1-yl)but-3-ene-1,2-dione;

1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione, or

1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione.

11. The compound according to claim 1 which is:

1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

4-(1-(3-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione;

1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

4-(1-(3-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalene-1-yl)piperazin-1-yl)but-3-ene-1,2-dione;

1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione;

1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione;

1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione;

1-(4-([1,1′-biphenyl]-4-yl)piperazin-l-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione;

1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;

1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione; or

1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione.

12. A pharmaceutical composition for treating TB, MDR-TB or XDR-TB, comprising a therapeutic amount of a compound according to claim 1 in combination with a pharmaceutically acceptable carrier, additive or excipient.

13. The pharmaceutical composition of claim 12 wherein said composition treats said TB infection by inhibiting TB DNA-dependent RNA polymerase, both wild type and mutants, in the human host.

14. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1, a pharmaceutically acceptable carrier, additive or excipient in combination with a therapeutically effective amount of at least one compound selected from the group consisting of: (i) another TB drug and/or a TB drug that is active against drug-resistant TB; (ii) a therapeutically effective amount of an agent for the treatment of AIDS; (iii) an anti-infective agent, (iv) an immunomodulator, (v) another bioactive agent selected from the group consisting of antibiotics, vaccines and an additional antiviral agent, and mixtures thereof.

15. The composition according to claim 12 in oral or parenteral dosage form.

16. The composition according to claim 12 formulated for administration as an inhalation spray or a rectal suppository.

17. A method of treating a TB infection in a patient, said method comprising administering to said patient an effective amount of a composition according to claim 12.

18. A method of treating a patient with TB comprising administering to said patient a therapeutically effective amount of a compound according to claim 1.

19. A method of inhibiting TB DNA-dependent RNA polymerase in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound according to claim 1.

20. The method according to claim 17 wherein said subject is a human.

21. The method according to claim 17 wherein said TB infection is caused by TB which is drug-resistant.

22. The method according to claim 21 wherein said drug-resistant TB is extensively drug-resistant TB (XDR-TB).

23. The method according to claim 21 wherein said drug-resistant TB is extremely drug-resistant TB (XXDR-TB).

24. A pharmaceutical composition comprising an effective amount of a compound according to claim 1 in combination with an effective amount of at least one additional anti-TB agent and optionally at least one anti-HIV compound, in combination with a pharmaceutically acceptable carrier, additive or excipient.

25. The composition according to claim 24 wherein said anti-HIV compound is combined with an anti-infective agent.

26. The composition according to claim 24 wherein said anti-HIV compound treats said TB infection by inhibiting at least TB DNA-dependent RNA polymerase, both wild type and mutants, in the human host.

27. The composition according to claim 24 in oral or parenteral dosage form.

28. The composition according to claim 24 formulated for administration as an inhalation spray or a rectal suppository.

29. A method of treating a TB infection in a human host comprising administering to said host in combination, an effective amount of at least one compound according to claim 1 in combination with at least one anti-HIV agent and at least one other anti-TB compound in combination with a pharmaceutically acceptable carrier, additive or excipient.

30. A method of treating a TB infection in a patient, said method comprising administering to said patient an effective amount of a composition according to claim 24.

31. A method of inhibiting TB DNA-dependent RNA polymerase in a subject, said method comprising administering to said subject a therapeutically effective amount of a composition according to claim 24.

32. The method according to claim 30 wherein said patient is a human.

33. A kit comprising a pharmaceutical composition according to claim 12 and instructions for a medical professional and/or a patient on how to administer said composition.